Glucocorticoid-dependent expression of O6-methylguanine-DNA methyltransferase gene modulates dacarbazine-induced hepatotoxicity in mice

Michiko Horiguchi, Jahye Kim, Naoya Matsunaga, Hiroaki Kaji, Takashi Egawa, Kazutaka Makino, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against the alkylating agent-induced cytotoxic lesion O 6-alkylguanine in DNA. Although a significant circadian variation in MGMT activity has been found in the liver of mice, the exact mechanism of the variation remains poorly understood. In this study, we present evidence that glucocorticoids were required for the 24-h oscillation of MGMT expression in mouse liver. The exposure of mouse hepatic cells (Hepa1-6) to dexamethasone (DEX) significantly increased the mRNA levels of MGMT in a dose-dependent manner. The DEX-induced increase in MGMT expression was reversed by concomitant treatment with RU486 [11β-[p-(dimethylamino) phenyl]-17β-hydroxy-17- (1-propynyl)estra-4,9-dien-3-one], a glucocorticoid receptor antagonist. The mRNA levels of MGMT and its enzymatic activity in the liver of mice showed significant 24-h oscillations, which were not observed in adrenalectomized mice. A single administration of DEX to adrenalectomized mice significantly increased the mRNA levels of MGMT in the liver. These findings suggest that the 24-h oscillation in the hepatic expression of MGMT is caused by the endogenous rhythm of glucocorticoid secretion. Dacarbazine (DTIC), a potent O6- guanine-alkylating agent, causes serious hepatotoxicity accompanied by hepatocellular necrosis and hepatic vein thrombosis. DTIC-induced hepatotoxicity in mice was attenuated by administering the drug at the time of day when MGMT expression was abundant. The present findings suggest that glucocorticoid- regulated oscillation in the hepatic MGMT expression is the underlying cause of dosing time-dependent changes in DTIC-induced hepatotoxicity.

Original languageEnglish
Pages (from-to)782-787
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number3
DOIs
Publication statusPublished - Jun 1 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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